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Background: Dysfunctional cellular mechanosensing appears central to aneurysm formation [1]. We aimed to derive material parameters of aneurysm tissue from in vivo deformations, which may increase insight into the underlying structural integrity of the pathological tissue. Methods: Videos of tracking markers (example Video in supplement, screenshot in Figure) placed on ascending aortic segments were captured alongside radial arterial blood pressure in patients undergoing open-thorax ascending thoracic aorta aneurysm (ATAA) repair (n = 5) and coronary bypass (controls; n = 2). Normalised cross-correlation was used to determine marker displacements, resulting in estimates of systolic/diastolic diameters, distensibility, and cyclic axial engineering strain. A thin-walled, cylindrical geometry was assumed, with amorphous (Neo-Hookean) and fibrous (two-family) constitutive contributions [2]. This framework was fitted to individual patient measurements, by varying parameters c (amorphous material constant), k1 and k2 (fiber stiffness and strain stiffening parameter), β (fiber angle w.r.t. circumferential direction), unloaded intact length (L), and internal radius (Ri). FigureLeft: Example of ascending aortic region of interest with tracking markers. Right: Data presented as mean ± standard deviation. SBP/DBP, systolic/diastolic blood pressure. Estimated properties are defined in the text. Results: Axial strain tended to be lower (expected) and distensibility larger (unexpected) in aneurysm than controls (Figure). However, the intrinsic pressure-dependence of distensibility must be considered when drawing conclusions related to differences in structural stiffness between both groups [3]. Material stiffness parameters (c and k1) appeared higher in aneurysm patients than in controls which is in line with previous studies in mice [4]. Conclusion: We are developing a method to determine ATAA material properties from in vivo deformations and observed increased material stiffness in ATAA.

Background: Arterial stiffness is a strong predictor of cardiovascular diseases and all-cause mortality [1]. Increased fasting plasma concentrations of highly reactive dicarbonyl compounds – methylglyoxal (MGO), 3-deoxyglucosone (3-DG), and/or glyoxal (GO) – may cause arterial stiffening via for mation of advanced glycation endproducts, triggering maladaptive responses in vascular tissue, e.g. elastin degradation and collagen cross-linking [2]. We assessed the cross-sectional associations between MGO, 3-DG, and GO concentrations with local carotid stiffness measures (distensibility coefficient (cDC), radius-wall thickness ratio (cRWT), pulse wave velocity (cPWV), and Young’s elastic modulus (cE) using standardized main variables. Methods: Fasting dicarbonyl concentrations were determined by ultra-performance liquid chromatography tandem mass spectrometry in EDTA plasma collected from 2275 participants (age: 60 ± 8 years, mean ± SD; 49% women, 605 with type 2 diabetes mellitus) of the Maastricht Study [3], an observational, population-based cohort study. Cross-sectional associations were assessed using multivariable linear regression analysis adjusting for age, sex, mean arterial pressure (MAP), heart rate, lifestyle factors, and medication. Since arterial stiffness measures are intrinsically pressure dependent, we additionally assessed the associations with pressure-corrected counterparts [4], instead of statistically correcting for MAP. Results: Fasting dicarbonyl concentrations were associated with arterial stiffening (smaller cDC; larger cPWV and cE) in most crude models, but not in adjusted models (Table). cRWT was associated with 3-DG, but only in the crude model. The use of pressure-corrected metrics did not materially change the final models. Model cDC cRWT cPWV cE α (95% CI) α (95% CI) α (95% CI) α (95% CI) MGO 0 –0.104(–0.145;–0.063) 0.011(–0.030;0.052) 0.103(0.062;0.144) 0.099(0.059;0.140) 1 –0.032(–0.070;0.005) 0.010(–0.032;0.052) 0.032(–0.006;0.071) 0.033(–0.007;0.072) 2 0.005(–0.029;0.039) 0.000(–0.042;0.042) –0.004(–0.039;0.030) –0.006(–0.042;0.030) 3 0.003(–0.031;0.037) 0.000(–0. 043; 0.042) –0.003(–0.038;0.032) –0.005(–0.040;0.031) 3-DG 0 –0.164(–0.205;–0.123) 0.067(0.026;0.108) 0.149(0.108;0.190) 0.171(0.131;0.212) 1 –0.102(–0.154;–0.051) 0.024(–0. 033; 0.082) 0.075(0.023;0.127) 0.093(0.039;0.147) 2 –0.037(–0.084;0.009) 0.009(–0.049;0.066) 0.012(–0.036;0.060) 0.027(–0.023;0.076) 3 –0.018(–0.065;0.029) –0. 004(–0.062; 0.054) –0.007(–0.056;0.041) 0.004(–0.045;0.054) GO 0 –0.054(–0.095;–0.013) –0.032(–0.074;0.009) 0.054(0.012;0.095) 0.038(–0.003;0.079) 1 –0.015(–0.051;0.022) –0.014(–0.055; 0.026) 0.015(–0.022;0.052) 0.008(–0.030;0.046) 2 0.002(–0.031;0.035) –0.015(–0.056;0.025) –0.002(–0.035;0.032) –0.008(–0. 042;0. 027) 3 –0.009(–0.042;0.024) –0.013(–0.053; 0.028) 0.011(–0.022;0.045) 0.005(–0.030;0.040) Model 0: crude associations. Model 1: model 0 + age, sex, and glucose metabolism status. Model 2: model 1 + mean arterial pressure and mean heart rate, and anti-hypertensive drugs. Model 3: model 2 + body mass index, smoking status, physical activity, use of lipid-modifying drugs, fasting triglycerides and total-to-high-density lipoprotein cholesterol levels, alcohol use, history of cardiovascular disease, kidney function, and Dutch healthy diet score. MGO, methylglyoxal; 3DG, 3-deoxyglucosone; GO, glyoxal; cDC, carotid distensibility coefficient; cRWT, carotid radius-wall thickness ratio; cPWV, carotid pulse wave velocity; cE, carotid Young’s elastic modulus. Significant associations (p < 0.05) printed in bold. TableAssociations between fasting plasma dicarbonyls and carotid stiffness measures Conclusion: Fasting plasma concentrations of either MGO, 3-DG, or GO are not independently associated with carotid stiffness in this cross-sectional analysis.

Background: Calibration of carotid artery tonometry waveforms needs to account for pulse pressure augmentation [1]. Due to its location nearer to the heart, carotid pulse pressure (carPP) is about 10 mmHg lower than brachial (brachPP) [1]. In practice, perfect applanation is hard to achieve with tonometry and thus tracking-errors may occur, leading to an exaggerated fall in the diastolic limb of the tonometry waveform. Consequently, the mean-to-diastolic difference of the waveform is underestimated, leading to an overestimation of carPP after calibration. We assessed the relationship between brachPP and carPP in 100 subjects, aged 18–80 yrs. Methods and Results: Brachial pressure (Omron) and carotid tonometry (Sphygmocor) measurements were performed by a single, highly skilled vascular technician, according to Artery Society methodological standards. CarPP was 5 ± 13 mmHg lower than brachPP. Bland-Altman analysis revealed a positive trend (r = 0.695, p < 0.0001) between the carPP–brachPP difference and their mean, with carPP being 20 mmHg lower than brachPP at a mean 40 mmHg which extended to carPP being 20 mmHg higher(!) than brachPP at a mean 80 mmHg. Accordingly, 30% of the study population showed unphysiological carPP, indicating an unrealistic i.e. reverse amplification. Even with a tolerance of +5 mmHg, still 20% of cases showed unrealistic values. Conclusion: In practice, calibrated carotid tonometry waveforms may yield unphysiological overestimations of carotid pulse pressure. This finding implies (potential) estimation errors in regression model studies on central pressure and local stiffness, suggesting brachial pulse pressure would be a valid compromise.

Greater very short- to mid-term blood pressure variability (BPV) has been associated with an increased CVD risk, especially stroke. However, this link remains incompletely understood. We hypothesized that increased arterial stiffness and maladaptive carotid arterial remodeling may underlie this association. We therefore investigated the association between very short- to mid-term systolic BPV, aortic and carotid stiffness and carotid arterial remodeling using cross-sectional data from The Maastricht Study (aged 60 ± 8 years; 53% men). Aortic (carotid-femoral pulse wave velocity, n = 1671) and carotid stiffness (ultrasonography, n = 1690) were assessed. A composite index of systolic BPV was derived by standardizing and averaging systolic within-visit, 24-hour, and 7-day BPV. We performed linear regression analyses with adjustment for age, sex, glucose metabolism status, mean arterial pressure and cardiovascular risk factors. A 1-SD greater systolic BPV was statistically significantly associated with 0.10 m/s (95%CI: 0.01 – 0.20) greater cfPWV, but not with carotid distensibility (−0.033·10-3/kPa [−0.255 – 0.190]). In addition, a 1-SD greater systolic BPV was statistically significantly associated with greater carotid circumferential wall tension (0.84 dyne/cm [0.51 – 1.17]), circumferential wall stress (0.79 kPa [0.031 – 1.27]) and intima-media thickness (8.6 μm [1.0 – 16.3]). These results are indicative of maladaptive carotid remodeling, as circumferential wall tension and stress were not normalized despite greater intima-media thickness. In conclusion, greater very short- to mid-term BPV is associated with greater aortic stiffness and maladaptive carotid arterial remodeling, but not with carotid stiffness. These findings may explain, at least partially, the increased BPV-associated CVD risk, in particular stroke.

Background: Vascular research demonstrated that pulse wave velocity (PWV), a measure of arterial stiffness, is inherently blood pressure-dependent. Considering the hypothesised pathophysiological chain of increased arterial stiffness leading to increased blood pressure load with consequent left ventricle hypertrophy (LVH) development, we conducted a systematic review of antihypertensive and lifestyle intervention studies to determine the association between on the one hand changes in arterial stiffness and blood pressure, and on the other hand changes in LV mass (LVM). Methods: Using PubMed, EMBASE, Cochrane and Web of Science, we identified 23 studies, containing 2573 patients. Studies reported changes in arterial stiffness (assessed by means of PWV), systolic- and diastolic blood pressure (SBP, DBP), and LVM index (LVMI), respectively. Results: Statistically significant reductions in SBP, PWV and LVMI were reported in 16, 14, and 20 studies, respectively. Pooled analysis of studies showed that the proportion in SBP reduction did not correlate significantly to the proportion in reductions of the other two variables. On the other hand, we found a significant positive correlation (r = 0.58, p = 0.007) between arterial stiffness and LVM regression, expressed as a relevant reduction in LVMI of 6.5 g/m2 per 1.0 m/s reduction in PWV. Conclusions: Our findings provide evidence that a decrease in arterial stiffness is associated with regression of LVH. To investigate whether there exists a causal relation between LVH due to arterial stiffness increases and in turn blood pressure load increases, future studies should strive for a multiple followup design and use of blood pressure-independent or -corrected stiffness indices.

Background: Pulse wave velocity (PWV) is quantified by time difference of arrival of the blood pressure (BP) wave at two sites along the arterial bed (transit time; TT-PWV), or by combining measured arterial pressure and diameter using the Bramwell-Hill equation (BH-PWV). Besides the dependence of PWV on BP, TT-PWV also depends on heart rate (HR). The present study aimed to also quantify the dependence of BH-PWV’s on HR, as a function of diastolic BP (DBP). Methods: Adult anaesthetised rats (n = 24) were randomly paced at 300–500 bpm, at 50-bpm steps. At each step, aortic TT-PWV (two pressure-tip catheters) and BH-PWV (pressure-tip catheter and ultrasound wall-tracking; abdominal aorta) were measured simultaneously, across a pharmacologically induced DBP range of 60–110 mmHg. Data from 9142 heart beats was analysed using mixed-effects modelling. Results: HR dependence of TT-PWV increased from 0.03 m/s/100 bpm at DBP = 60 mmHg to 0.06 m/s/100 bpm at DBP = 110 mmHg (both p ≤ 0.023). HR dependence of BH-PWV was 0.11 m/s/100 bpm at DBP = 60 and 85 mmHg, but paradoxically decreased to 0 at DBP = 110 mmHg (p = 0.686). This decrease in dependence is explicable in that standard BH-PWV uses an approximate derivative of pressure to diameter, which overestimates PWV with increasing pulse pressure (PP). PP decreases as HR increases, potentially causing a BH-PWV decrease with HR. This effect can be overcome by estimating the full pressure-diameter curve for each HR, and calculating the true derivative at DBP, yielding a BH-PWV that no longer shows significant HR dependence (p ≥ 0.076 at all DBPs). Conclusions: BH-PWV and TT-PWV show a different HR dependence, affected by DBP.

Objectives: Arterial stiffness index β and cardio-ankle vascular index (CAVI) are widely accepted to quantify the blood pressure (BP)-independent, intrinsic exponent (β0) of the BP-diameter relationship. CAVI and β assume an exponential relationship between pressure (P) and diameter (d). We aim (1) to demonstrate that, under this assumption, β and CAVI as currently implemented are inherently BP-dependent and (2) to provide corrected, BP-independent forms of CAVI and β. Methods and results: In P=Pref*exp[β0(d/dref−1)], usually reference pressure (Pref) and reference diameter (dref) are substituted with diastolic BP and diameter to accommodate measurements. Consequently, the resulting exponent is not equal to the pressure-independent β0. CAVI does not only suffer from this reference pressure effect, but also from the approximation of dP/dd. For example, assuming β0=7, an increase of systolic/diastolic BP from 110/70 to 170/120 mmHg increased β by 8.1% and CAVI by 14.3%. We derived corrected forms of β and of CAVI (CAVI0) that did not change with BP and represent the pressure-independent β0. To substantiate the BP effect on CAVI in a typical follow-up study, we realistically simulated patients (n=161) before and following BP-lowering treatment (assuming no follow-up change in intrinsic β0 and therefore in actual P-d relationship). Lowering BP from 160±14/111±11 to 120±15/79±11 mmHg (p

Background: We recently found in patients that the pressure dependency of arterial stiffness is age-dependent, explaining clinically observed changes in stiffness with blood pressure (BP) lowering. Pulse wave velocity, BP and age found in the Reference Values for Arterial Stiffness Collaboration show a corresponding pattern. We hypothesised that the impact of age on the pressure-dependency of arterial stiffness actually reflects changes in wall constituent properties and adaptation to mechanical stress Methods and results: We applied a constitutive model of arterial wall biomechanics (Zulliger, AJP-Heart 2004) to simulate ageing, based on detailed pressure-area curves obtained in our younger (mean age 40 yrs, n=6) and older (65 yrs, n=7) hypertensive patients. Ageing was simulated by adapting the model (initially fitted to the "young" pressure-area curve) to fit the "old" curve (Figure); allowing for elastin degradation, collagen rearrangement and wall thickness adaptation, but not for changes in fractional volumes. The simulation showed a physiologically significant transfer of pressure-load bearing from elastin to collagen, caused by a 40% loss in elastin stiffness and a 5-fold increase in collagen recruitment (Table). Presuming normalisation and homogeneous distribution of wall stress with ageing, the predicted increase in wall thickness was in accordance with intima-media thickness Reference Values (2010 data; 25-yr increment, corresponding risk category). Conclusion: Ageing influences observed arterial stiffness values at given blood pressures through underlying changes in the properties and mechanical loading of arterial wall constituents.

The role of ventricular–arterial hemodynamic interaction in the occurrence of arterial dissection and rupture in vascular Ehlers–Danlos syndrome (vEDS) is unknown. We recently introduced an ultrasound-based method to extract, from common carotid artery (CCA) diameter waveforms, central arterial properties and left ventricular (LV) systolic time intervals. We obtained CCA diameters, compliance and distensibility coefficients, and LV isovolumic contraction and ejection periods (ICP and EP) of 19 vEDS patients (aged 27–65 yrs) and 19 age-matched healthy controls. CCA distension and compliance tended to be lower in vEDS subjects (p = 0.062 and p = 0.073), especially in younger patients. ICP (−12 ms) and EP (−24 ms) were shorter (p < 0.001), while heart rate was increased (+10 bpm; p < 0.001) in vEDS. The ICP/EP ratio and estimated isovolumic dPLV/dt indicated increased LV contractility in vEDS. In conclusion, vascular EDS patients tend to have a lower CCA compliance but a normal pulse pressure, most likely reflecting reduced physical fitness.

Results: As expected, clinic blood pressure values and media to lumen ratio were higher in essential hypertensive patients than in normotensive controls. Fibronectin media content was significantly greater in essential hypertensive patients (7.41 2.28 %), compared with normotensive controls (5.62 0.40, P